DESCRIPTION: Applicant's Abstract We are proposing a placebo-controlled clinical trial to evaluate the efficacy and potential mechanisms of action of disulfiram (vs. placebo) for treating cocaine abuse in buprenorphine maintained subjects (N=180) with concurrent opiate dependence and cocaine abuse or dependence. Because of its safety in overdose situations and decreased abuse liability, buprenorphine may be widely used outside of narcotic treatment programs (e.g., in primary care or office settings). Thus it is of considerable importance to evaluate adjunctive pharmacologic treatments that may improve its efficacy for treating concurrent opioid and cocaine dependence. Convergent findings from epidemiologic, laboratory and clinical trials, including the results of a preliminary study conducted in preparation for this application, support the potential efficacy of disulfiram; a medication used to treat alcohol dependence, for the treatment of cocaine abuse. Disulfiram's efficacy for cocaine may result from preventing concurrent alcohol use, which can precipitate cocaine relapse, or from its inhibition of dopamine-beta-hydroxylase, the enzyme that converts dopamine to norepinephrine, which may reduce craving and increase the anxiogenic or dysphoric effects of cocaine administration. Accordingly, to explore whether disulfiram efficacy for cocaine dependence is mediated by its effects on alcohol consumption or on central DBH and dopamine activity, baseline alcohol severity, and DBH genotypes which are associated with high or low DBH activity will be evaluated as predictors of differential treatment response. Subjects meeting DSM-IV criteria for opioid dependence and cocaine abuse or dependence will be stabilized on buprenorphine (24 mg daily, sublingual tablets) for 2 weeks before being randomly assigned to 12 weeks of treatment with disulfiram 250 mg daily or placebo, provided under double-blind conditions. An urn randomization procedure will be used to balance the treatment groups on gender, depressive symptoms, baseline alcohol use and cocaine use severity. Manual-guided group drug counseling will be the platform psychotherapy provided weekly for all subjects. Primary outcome measures include reductions in cocaine use assessed by three times weekly urines and self-report. Secondary outcomes measures include reductions in illicit opioid use and HIV risk behaviors. Primary data analyses will focus on an intention-to-treat sample and will utilize mixed models analysis of variance and a factorial analysis of variance. The effects of baseline predictors and their interactions with treatment condition on these outcomes will also be evaluated.